This is an interdisciplinary program project designed to determine genetic and environmental influences upon craniofacial malformations. This information is currently unavailable and is urgently needed. The basic objective of the program is to investigate regulatory mechanisms operating in specialized tissues during critical stages of craniofacial development (e.g., first branchial arch-derived structures including mandibular morphogenesis, tooth morphogenesis, secondary palate formation and middle ear development). The major thrust of the program is to utilize steroid-induced congenital malformations in susceptible and resistant inbred strains of mice. This animal model system as well as osteopetrotic mice will enable a large number of significant questions to be addressed including: (1) Epigenetic regulation of enamel protein synthesis during epithelial-mesenchymal interactions, (2) Steroid receptors in craniofacial teratology, (3) Mandibular morphogenesis: embryonic, fetal, neonatal and postnatal development, (4) Embryonic basal lamina: composition, biosynthesis, remodeling and functions in development, and (5) Mechanisms of bone remodeling and osteoclast differentiation. Immunogenetic, biochemical, embryological, immunological and morphological criteria are integrated in order to implement our research program designs. This integrated effort will result in substantive advances in understanding of congenital craniofacial malformations and will clarify mechanisms of teratogenesis in pre- and postnatal life. This information will be utilized to ultimately reduce the frequency of craniofacial anomalies resulting from drugs and environmental chemicals.